Apparatus for measuring a chemical entity in a liquid

ABSTRACT

Apparatus for measuring or detecting a chemical entity in a liquid sample, the apparatus including a first module operationally connected to a second module, the first module having a flow passage for the sample, the flow passage including a sensor for measuring or detecting the chemical entity and .Iadd.a .Iaddend.pump .[.means.]. for advancing the sample along the flow passage, the second module including .[.means.]. .Iadd.an actuator .Iaddend.for actuating the pump means, and the second module being connected to the first module via .[.connecting means.]. .Iadd.a connector .Iaddend.permitting disconnection of the first and second modules and connection of a replacement first module to the second module.

This application is a continuation of Ser. No. 695,100 filed Jan. 25,1985, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to the measurement of chemical entities in liquidsamples.

A wide variety of analytical systems are available for measuringchemical entities such as ions, e.g., potassium, sodium, and chloride;gases, e.g., O₂ ; and organic compounds, e.g., glucose, in liquidsamples such as blood, urine, and liquids related to industrialprocesses. Such systems contain components which from time to timerequire maintenance or replacement.

SUMMARY OF THE INVENTION

In general, the invention features apparatus for measuring or detectinga chemical entity in a liquid sample, including a first moduleoperationally connected to a second module, the first module having aflow passage for the sample including a sensor for measuring ordetecting the chemical entity and pump means for advancing the samplealong the flow passage, and the second module having means for actuatingthe pump means, the two modules being connected via means permittingdisconnection and replacement of the first module.

In preferred embodiments, the sensor is capable of successivelyanalyzing a plurality of samples; the first module includes a pluralityof different sensors for measuring a plurality of different chemicalentities in the sample; the pump means is located downstream from thesensor; and the first module further includes a waste chamber forholding the sample after the chemical entity has been measured, and aholding chamber for a calibrating reagent, whose passage into the flowpassage is controlled by a selector valve which also controls intake ofthe sample into the flow passage, and which is actuated by meanscontained in the second module.

The flow-through apparatus of the invention provides all of thecomponents which come into contact with the sample--the flow passage,sensors, and pump--as well as the depletable calibration reagent, in asealed, disposable cartridge which, after it has been used to carry outa predetermined number of tests (e.g., sodium and potassium measurementson 100 whole blood or serum samples), is disposed of in its entirety andreplaced. The user (e.g., a physician using the apparatus in his office)does not need to learn how to maintain the electrodes or the pump, orkeep reagents on hand to refill reagent containers (a procedure whichalso carries with it the possibility of the introduction ofcontaminants, or the refilling of a container with the wrong reagent.)

Another advantage of the apparatus of the invention is that thedisposable cartridge obviates expensive, time-consuming, and potentiallycontaminant-introducing preventive maintenance involved in the cleaningand/or replacement not just of reagents but also of the sensors, tubing,and other flow path elements, which would otherwise need to be kept instock to be available when needed, and which would require, forservicing, the ready availability of trained service personnel, to bothrecognize the need for, and provide, such servicing.

An additional advantage of the apparatus of the invention is that theshort, nearly horizontal flow path of the disposable cartridge preventsthe development of a fully laminar flow path, which could otherwiseresult in measurement errors.

Other features and advantages of the invention will be apparent from thefollowing description of the preferred embodiment thereof, and from theclaims.

DESCRIPTION OF THE PREFERRED EMBODIMENT

The drawings will first briefly be described.

DRAWINGS

FIG. 1 is a diagrammatic representation of measurement apparatus of theinvention;

FIG. 2 is a plan view of the top and bottom portions of apparatus of theinvention;

FIG. 3 is a bottom plan view of a portion of the apparatus of FIG. 2;

FIGS. 4 and 5 are side sectional views of portions of said apparatus;

FIG. 6 is a perspective view of a portion of said apparatus;

FIG. 7 is a sectional view taken at 7--7 of FIG. 6;

FIG. 8 is a perspective view of an electrode assembly of said apparatus.

STRUCTURE

Referring to FIG. 1, analyzing apparatus 10 includes first module 12,connected to second module 14 such that module 12, a disposablecartridge, can be replaced periodically.

First module 12 contains a sample flow passage including, beginningupstream, sample inlet port 18; photosensor 49; flow cell 22, containingelectrodes 24; and waste chamber 26. Reagent holding chambers 28 and 29communicate with rotary selector valve 20 via passages 30 and 31. Flowcell 22 also includes, downstream from electrodes 24, rotary valve 32which communicates with pump 34 via passage 39, and with referencechamber 78 via passage 37.

Second module 14 includes valve motor 36, computer 38 associated withdisplay screen 40, and pump motor 42. Valve motor 36 is operativelyconnected to valves 20 and 32, via activator shafts 54. Pump motor 42 isoperatively connected to pump 34 via pump cam 77. Electrodes 24 andreference chamber 78 are connected to computer 38 via electricalconnections 48, and motors 36 and 42 are connected to computer 38 viaelectrical connections 50 and 52, respectively.

Referring now to FIG. 2, there is shown apparatus 10 taken apart, aswhen module 12 is to be replaced; the top portion of module 14(containing the motors and computer) is shown in plan topside down, andmodule 12 and the bottom portion of module 14 (serving as a holder formodule 12) are shown in plan. Module 12 fits into the bottom portion ofmodule 14 such that the flat surface of each is flush with the other.The top portion of module 14 fits onto the bottom cartridge holderportion via snap connector posts 17, which mate with holes 15. Valveshafts 54 mate with valves 20 and 32.

Module 12 also includes vent 13 and six electrical connections 19, whichmeet pogo pin connections 100 in the top of module 14. As shown in FIG.2, two of the connections are connected to contact points 82 from thetwo electrodes of the electrode assembly (FIG. 8) via wires 33; one tosilver/silver chloride wire 43 from reference chamber 78; and three tothe connection 47 to photosensor 49 at the entrance to flow passage 18.Module 12 further includes reagent inlet tubes 56 and 58 from reagentchambers 28 and 29, respectively; waste tube 64, leading to wastechamber 26 (which contains a disinfectant); reference tube 65 leading toreference chamber 78; and pump tube 45, leading to pump 34 (FIG. 1).Four vent tubes 51 connect chambers 28, 29, 26, and 78 with vent 13.Also shown is diaphragm 71 of pump 34. Slot 21 is large enough to permitthe finger of the user to reach into module 14 to remove module 12 andthen insert its identical replacement.

FIG. 3 is a bottom plan view of module 12, showing reagent chambers 28and 29, reference liquid chamber 78, and waste chamber 26, surroundingthe other three chambers.

FIG. 4 is a side sectional view of module 12, showing the positioning ofthe chambers below the remainder of the module.

FIG. 5, a side sectional view of apparatus 10 above the level of thereagent chambers and through the center of the flow passage, illustratesthe relationship between motors 36 and 42 of module 14, and flow cell 22and the remaining portion of the flow passage of module 12. Motor 36drives Teflon and plastic rotary valves 20 and 32 via 3-poition, 45°Geneva mechanism 76, connected to the valves via valve shafts 54.

Motor 42 is connected via pump cam 77 to pump 34, which is made up ofshaft 73, plunger 72, flexible diaphragm 71, and pump chamber 70; shaft73 and plunger 72 are components of module 14, while diaphragm 71 andchamber 70 are components of module 12. Motors 42 and 36 are both CannotPF55 series stepping motors. Flow cell 22, which is cast of flexiblesilicone rubber, makes nipple connection 39 with the remainder of module12, at the point of continuation of the flow passage.

FIG. 6 illustrates flow cell 22 and its connection to the remainder ofapparatus 10. Slot 41 holds electrode assembly 80 (FIG. 8). All tubesmate with openings in flow cell 22 via nipple connections. Opening 63 isadapted to receive glass capillary tube 67.

FIG. 7, taken at 7--7 of FIG. 6, shows passages of flow cell 22,including the upstream (19) and downstream (39) portions of the flowpassage, reagent passages 30 and 31, waste passage 35, and referencepassage 37.

Referring to FIG. 8, molded polyvinylchloride (PVC) electrode assembly80 includes electrical connection points 82, connected to silver/silverchloride electrode wires 81 in the electrolyte solution of eachelectrode; two recessed, electrolyte-containing chambers 84; coveredwith flat, ultrasonically welded plastic plates 86; flow passage 88,including a sensor section including inlet and outlet ports 90 and 92,respectively; and integrated cast PVC, potassium ion selective andsodium ion selective membranes 94 flush with the remainder of the flowpassage. The potassium ion selective membrane was made generally asdescribed in Mikrochim, Acta (1980) Vol. II, page 309, and the sodiumion selective membrane was made generally as described in Auber et al.(1983) Clin. Chem. 29(8), 1508.

OPERATION

Referring to the Figures, to analyze a blood sample for potassium andsodium concentration, the sample is placed in capillary tube 67, whichis inserted into the apparatus, triggering photosensor 49, whichactivates computer 38, which has been programmed to activate motors 36and 42 to automatically take the sample through one measuring cycle, andto receive and process generated data. The computer and its software arenot included in the present invention. In the illustrated embodiment,they are shown contained in module 14; they could just as well be in aseparate module electrically connected to module 14.

The potassium and sodium ion concentrations of calibration reagent 28,sample, and calibration reagent 29, are measured sequentially. Eachliquid is drawn into the flow path to contact the electrodes by theaction of valves 20 and 32, and of pump 34. Motor 36, through Genevamechanism 76, drives both valve 20, the position of which determineswhether the sample, calibration reagent 28, or calibration reagent 29enters the flow cell, and valve 32, the position of which determines theflow cell's communication with the pump, the reference chamber, and thewaste chamber. The pump determines fluid volume in the flow cell, andmoves up and down mechanically independently of the valves.

The electrochemical potentials of the sample and the calibrationreagents are determined with reference to the reference liquid which,prior to each measurement, meets the liquid being analyzed in thedownstream region 39 of the flow passage to create a liquid junction.The generated signals (electrical potentials) are then amplified anddigitalized via an analog/digital converter; the activity of each ion isautomatically calculated using the Nicolsky equation.

The first step in the process is a calibration analysis of thecalibration reagent 28 remaining in the flow passage from the previousmeasurement; this is an isotonic sodium and potassium chloride reagent.After this measurement has been made, the sample fills the flow passageand is analyzed. Next, sodium and potassium chloride calibration reagent29 enters and is analyzed, and then additional calibration reagent 28enters and is analyzed, and remains for the start of the next cycle.

The measurements of the two calibration reagents serve to calibrate theelectrodes, to act as a check on instrument functions, and to flush thesystem between samples. The salt solutions in chambers 28, 29, and 78are all standard solutions used for these purposes by persons ofordinary skill in this field; their composition and method ofpreparation are given in Osswalt et al. page 74, in Lubbers et al.(1981).

PROGRESS IN ENZYME AND ION SELECTIVE ELECTRODES (Springer-Verlag).

Each liquid, after is has been analyzed, is ejected to waste chamber 26.As reagents and reference solution are depleted, air enters the chambervia vent 13; each chamber (i.e. chambers 26, 28, 29, and 78) isseparately vented.

After a predetermined number of samples have been analyzed (whenreagents have been exhausted), the user opens the top of module 14,reaches into opening 21, lifts out module 12, discards it, drops in areplacement module 12, and closes the top portion of module 14. Valveshafts 54 reversibly mate with valves 20 and 32, and electrical contactpoints 19 make contact. At this point, the apparatus is ready for use,with none of the components which contact the sample having beenretained, cleaned, serviced, or touched by the user.

OTHER EMBODIMENTS

Other embodiments are within the following claims.

For example, the number of measurements made on each sample can be aslow as one, or there can be measurement of considerably more than twochemical entities. Measurements of different chemical entities can becarried out at the same point in the flow passage, as in theabove-described embodiment, or sequentially along the flow passage. Anychemical measurements can be made, using any chemical sensors; inaddition to ion selective electrodes, measurements can be made using,e.g., pH electrodes, enzyme electrodes, or antibody/antigen sensors. Anyliquid sample can be analyzed, e.g., urine, cerebrospinal fluid,industrial effluents, or drinking water. Any pump configuration can beused, e.g., peristaltic roller pumps, and the pump means can be locatedanywhere in the flow path, e.g., upstream rather than downstream fromthe sensor. One, rather than two, calibration reagents, can be used, andin some instances more than two or no calibration reagent will berequired. The module containing the motors can be of any suitableconfiguration, e.g., all one piece, or two hinged parts. Any othervalves, including check, poppet or squeeze valves, can be used; and anyactuating means, e.g., other motors, electromagnetic actuators such assolenoids, or spring arrangements, can be used. Each valve and the pumpcan be driven by its own actuator, or one actuator can be used to driveall of them.

What is claimed is:
 1. Apparatus for measuring or detecting a chemicalentity in a liquid sample, said apparatus comprising a first moduleoperationally connected to a second module,said first module comprisinga flow passage for receiving at least one liquid sample and havingreagent containing means, of sufficient size with sufficient reagent to.[.mix with.]. .Iadd.analyze .Iaddend.a plurality of samples enteringsaid flow passage to allow for successive analysis of a .[.plurlaity.]..Iadd.plurality .Iaddend.of samples, and having flushing fluidcontaining means said flow passage including a sensor section includingsensor means for contacting fluid comprising a liquid sample .[.and.]..Iadd.or .Iaddend.reagent to measure or detect a chemical entity of thefluid while establishing a noncontaminating relationship with saidsecond module and said first module including pump means for advancingthe sample along said flow passage and actuating said flushing fluidcontaining means, thereby flushing said first module between analysis ofsuccessive samples, said second module comprising means for actuatingsaid pump means, said second module being connected to said first modulevia connecting means permitting disconnection of said first module fromsaid second module and connection of a replacement first module to saidsecond module, and wherein .Iadd.said .Iaddend.first module is in theform of a sealed disposable cartridge.
 2. The apparatus of claim 1wherein said sensor means of said first module comprises a plurality ofdifferent sensors for measuring a plurality of different chemicalentities in a sample.
 3. The apparatus of claim 1 wherein said pumpmeans is located downstream from said sensor section.
 4. The apparatusof claim 1 wherein said first module includes, downstream from saidsensor section, a waste chamber for holding a sample after said chemicalentity in the sample has been detected or measured.
 5. The apparatus ofclaim 1 wherein said apparatus further comprises at least one referencechamber containing sufficient reference solution for analysis of aplurality of samples.
 6. The apparatus of claim 1 wherein said flowpassage of said first module includes, upstream from said sensorsection, a sample inlet port for introducing the liquid sample into saidfirst module.
 7. The apparatus of claim 6 wherein said flow passageincludes, downstream from said sample inlet port and upstream from saidsensor section, a selector valve for controlling the intake of a sampleinto said flow passage, and wherein said second module includes meansfor actuating said selector valve.
 8. The apparatus of claim 7 whereinsaid first module further comprises a holding chamber for holding acalibrating reagent, said holding chamber being connected to said flowpassage, and passage of said calibrating reagent into said flow passagebeing controlled by said selector valve.
 9. A replaceable module in theform of a disposable cartridge for use in apparatus for measuring ordetecting a chemical entity in a liquid sample that establishes anon-contaminating relationship with said apparatus, said replaceablemodule comprising a flow passage for receiving at least one liquidsample, and having reagent containing means of sufficient size withsufficient reagent to .[.mix with.]. .Iadd.analyze .Iaddend.a pluralityof samples entering said flow passage to allow for successive analysisof a plurality of samples, and having a flushing fluid containing means,and wherein said flow passage includes a sensor section including sensormeans for contacting fluid comprising a liquid sample .[.and.]. .Iadd.ora .Iaddend.reagent, allowing for measuring or detecting a chemicalentity of the fluid, said module including pump means for advancing thesample along said flow passage and actuating said flushing fluidcontaining means, thereby flushing said module between analysis ofsuccessive samples.